This is an investigation of the clinical pharmacology of a tricyclic antidepressant in humans. The methodology involves multiple administration of a constant, oral dose of imipramine to a large sample of depressed patients. Serial measure of affective state will be recorded over the same period of time that the plasma levels of imipramine and desmethylimipramine will be determined. The major objective of the study is to establish the character of the variability in plasma steady-state level of a tricyclic antidepressant and to examine the relationship between this variability and clinical outcome. In addition, a series of interrelated questions will be examined. These are: the contribution of pharmacodynamic factors to the interindividual plasma steady-state level variability; the usefulness of metabolism markers in predicting the eventual steady state concentration of imipramine; the extent to which low plasma levels contribute to apparent treatment failures; and the relationship between plasma levels and clinical outcome across varying depressive typologies. At the same time and in the same patient population an examination will be made of the possible association between the administration of imipramine and cardiac toxicity, particularly, in relation to pre-existing cardiac disease.